Periodontal diseases are a group of infections that affect the structures surrounding teeth, mainly including gingivitis and periodontitis. The most common form of periodontal diseases is gingivitis, which is highly prevalent and can affect up to 90% of the worldwide population. Both clinical and basic studies have shown that the oral spirochete Treponema denticola (Td) is strongly associated with human periodontal and endodontic diseases, such as acute necrotizing ulcerative gingivitis, early-onset and chronic periodontitis, orofacial abscesses, and periapical radiolucencies. Previous studies have shown that Td is able to induce the actin rearrangement and detachment of human epithelial cells and gingival fibroblasts. However, the corresponding virulent factor(s) has not yet been identified. Zonula occludens toxin (Zot) was originally identified in Vibrio cholerae. This toxin is able to increase the permeability of the small intestine by affecting the structure of the intercellular tight junctions. In preliminary studies, a putative Zot-like toxin (TDE0298) was found in the genome of Td;and further studies have shown that this putative toxin is able to induce the cytoskeletal rearrangement of human gingival fibroblasts. Based on these data, we hypothesize that TDE0298 is a Zot-like toxin that may contribute to the tissue invasiveness and virulence of Td by modulating cytoskeletal components in human gingival cells. To test this hypothesis, the proposed studies will focus on the following specific aims: Aim 1#: To determine if TDE0298 possesses toxic characteristics similar to V. cholerae Zot;Aim 2#: To investigate the molecular mechanism of the actin reorganization induced by TDE0298;Aim 3#: To determine the role of TDE0298 in the virulence of Td in vitro and in vivo. Zot-like toxin has not been reported in any oral pathogens. The proposed studies will help us to understand the cytotoxicity of this toxin and the potential molecular mechanism involved in its action, as well as its role in the pathogenesis of Td. The achievement of the proposed goals may eventually lead to new means of prevention and treatment for periodontal infections. PUBLIC HEALTH RELEVANCE: Periodontal diseases can affect up to 90% of the worldwide population, which are primarily caused by polymicrobial infections. Oral spirochete Treponema denticola is strongly associated with human periodontal and endodontic diseases. The goal of this proposal is to investigate the role of a putative Zot-like toxin in the pathogenesis of T. denticola.